Estrogen Maintains Pregnancy, Triggers Fetal Maturation

For a long time, reproductive endocrinologists have watched estrogen levels climb during pregnancy, but they did not know what all that estrogen did.

Now, nearly two decades after publishing their first paper on estrogen's role in pregnancy, Dr. Eugene D. Albrecht, a University of Maryland School of Medicine professor of obstetrics/gynecology and reproductive sciences, and his colleague, Dr. Gerald J. Pepe, professor of physiology at Eastern Virginia Medical School, have mapped the intricate interactions of estrogen, progesterone and other hormones during fetal development. Their research explains how estrogen helps maintain pregnancy and stimulates the vital process of fetal maturation .

With one hormone triggering the production of another, which in turn regulates the development and release of still others, and with cells changing structure and function as they mature, it's a complicated story. But the researchers' conclusions can be summarized simply: Estrogen regulates progesterone, protecting pregnancy. It also kick-starts one of the major processes of fetal maturation. Without it, a fetus's lungs, liver and other organs and tissues cannot mature.

Speaking at the Society for Gynecologic Investigation's annual scientific meeting in San Diego on March 22, Albrecht and Pepe outlined their research into what they call the "fetal-placental dialogue" and how it regulates the differentiation of cells that develop into the placenta and fetal adrenal glands, essential elements in the nourishment, maturation and development of a fetus.

"Our research has uncovered several roles for estrogen," Albrecht said. "One is to maintain pregnancy, which it may do by regulating the production of progesterone.

Albrecht, a perinatal endocrinologist, told the obstetric and gynecologic researchers that the placenta and fetus communicate extensively with each other with respect to growth and development. And estrogen is in the driver's seat.

Albrecht and Pepe's estrogen research focuses on the activation of what they call the placental corticosteroid pathway and its impact on the fetal adrenal glands. These glands, located above the kidneys, produce cortisol, a steroid hormone critical for maturation of the lungs, liver and other organs and tissues of the developing fetus.

Another hormone known as ACTH (for adrenal corticotropic hormone) produced by the pituitary - a small gland at the base of the brain - stimulates cortisol production.

Through much of pregnancy, cortisol passes through the placenta from mother to fetus, suppressing fetal pituitary ACTH, so that the fetus cannot produce its own cortisol, Pepe explained. Studying live, pregnant baboons - primates whose endocrinology during pregnancy is similar to that of humans - the scientists found that fetuses do start producing their own cortisol two-thirds of the way through pregnancy.

"What we didn't know is what triggers this process," Albrecht said.

Now they do. The trigger is estrogen. Albrecht and colleagues discovered that by doubling their baboons' estrogen levels halfway through pregnancy, they activated the cortisol production process in the developing fetus. Then they blocked estrogen with an enzyme antagonist that inhibits production of estradiol, the most potent of the estrogens. In the fetuses where estrogen was blocked, the cortisol pathway never developed.

Doubling the amount of estrogen also speeded up the transformation of the stem cells of the placenta into mature cells whose structure and function is quite different, Albrecht said. Blocking estrogen resulted in miscarriage.

Clinically, Albrecht and Pepe's findings could lead to a new outlook on the role that estrogen plays in pregnancy, the relationship of estrogen to maturation and development of the fetus and placenta, and the problem of miscarriage.

Albrecht and Pepe's consortium research is funded by the National Institute of Child Health and Human Development, National Institutes of Health.